Putting the Efficacy of Candesartan Cilexetil Into Perspective

Journal of Human Hypertension (2000) 14, Suppl 2, S33–S41 2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh Putting the efficacy of candesartan cilexetil into perspective: a review of new comparative data JM Mallion and JP Baguet CHU Hoˆ pital Michallon, Me´decine Interne et Cardiologie, Grenoble, France Candesartan is one of the first angiotensin II receptor tions that can be made between the AIIRAs in terms of antagonists (AIIRAs) to be developed. It binds tightly to their pharmacokinetic profiles, the antagonistic potency and dissociates slowly from the angiotensin subtype 1 of candesartan cilexetil at the AT1 receptor over 24 h (AT1) receptor in vitro. These binding characteristics dif- clearly differentiates it from other members of its class. fer from those of losartan, which demonstrates lower These differences are reflected in the antihypertensive affinity and faster dissociation from the AT1 receptor. efficacy and duration of action of candesartan in clini- Candesartan causes long-lasting antagonism of the vas- cal trials. cular contractile response to angiotensin II compared Journal of Human Hypertension (2000) 14, Suppl 2, S33– with irbesartan, losartan or the active metabolite of los- S41 artan – EXP-3174. While there are relatively few distinc- Keywords: candesartan cilexetil; angiotensin II AT1-receptor antagonist; antihypertensive treatment; comparative efficacy review Introduction the basis of their improved oral bioavailability and 6 potency at the AT1 receptor (Figure 1). Since the Angiotensin II receptor antagonists (AIIRAs) rep- introduction of the prototype losartan in 1994, new resent an important new class of antihypertensive agents such as candesartan cilexetil, valsartan, agents which enable a more specific and complete irbesartan, telmisartan and eprosartan have been block of the renin-angiotensin system (RAS) com- made available. These agents have been shown to pared with angiotensin-converting enzyme (ACE) combine blood pressure-lowering efficacy – compa- inhibitors. The AIIRAs selectively block the angi- rable with ACE inhibitors and calcium channel otensin subtype 1 receptor (AT ), which mediates 1 blockers – with a tolerability profile comparable most of the known actions of angiotensin II. The development of AIIRAs has overcome some with placebo. In addition to, and perhaps inde- of the difficulties apparent with ACE inhibition. pendent of, their antihypertensive action, their Regardless of whether the angiotensin II is produced potent inhibition of the RAS is expected to bring by ACE or ACE-independent pathways, such as additional benefits for the management of heart tissue chymase, chymostatin-sensitive angiotensin failure and renal disease (associated with diabetes II-generating enzyme (CAGE), cathepsin G and mellitus). others,1,2 the AIIRAs cause a highly specific block When used once daily, either as monotherapy or of the angiotensin II at its receptor. Although ACE in combination with other antihypertensive agents, inhibitors are efficacious and have relatively few the AIIRAs are effective for the management side effects,3 the lack of specificity of ACE inhibition of patients with mild, moderate and severe hyper- results in a potentiation of endogenous kinins tension. As well-tolerated antihypertensive agents, (bradykinin and tachykinin) associated with class- the AIIRAs are important new tools for the primary specific side effects such as angioedema and dry prevention of cardiovascular morbidity and cough.4 mortality. In the early 1980s, Takeda Chemical Industries, This paper reviews new data, comparing the phar- Ltd5 described the first non-peptide derivatives macodynamics and clinical efficacy of candesartan angiotensin antagonists (CV-2198, CV-2973 and cilexetil with the other members of this new class. CV-2961), which were considered specific but weak While all of these drugs are highly selective for the antagonists at the AT1 receptor. These molecules AT1 receptor, there are important differences in their served as structural templates for the development pharmacology, pharmacokinetics and pharmacody- of a series of new compounds that were selected on namics that are reflected in their duration of antihypertensive effect. In particular, they differ in affinity constants, especially dissociation constants from the Correspondence: Professor JM Mallion, CHU Hoˆpital Michallon, receptor, antagonism characteristics and in vivo Me´decine Interne et Cardiologie, BP 217, 38043 Grenoble Cedex 09, France. Tel: + 33 476 76 54 40, Fax: + 33 476 76 55 59 pharmacodynamics. The comparative efficacy of candesartan JM Mallion and JP Baguet S34 Figure 1 Discovery and development of selective non-peptide angiotensin II receptor antagonists. Differential preclinical pharmacology of artan was the most potent of the AIIRAs tested; AIIRAs potencies were candesartan у irbesartan Ͼ EXP- 3174 Ͼ eprosartan and valsartan. Receptor binding affinity and specificity Like all the AIIRAs in clinical development, candes- Antagonistic properties artan is a potent and selective AT1 receptor blocker. The angiotensin II-mediated vascular contractile Candesartan dose-dependently inhibited the in vitro responses in isolated rat portal vein and rabbit aorta binding of radiolabelled angiotensin II at the AT1 in the presence of AIIRAs have been investigated receptor in rabbit aorta but did not interact with the independently by a number of research groups.10– angiotensin subtype 2 (AT2) receptor in the bovine 15 These studies have found that while candesartan Ͼ cerebellum. Candesartan had a 10 000-fold higher (0.01–1 nM) produces a clear dose-dependent affinity for the AT1 receptor compared with the AT2 reduction in the maximal contractile response to 7 receptor. The affinity of candesartan for the AT1 angiotensin II (characteristic of insurmountable or receptor was 80 times greater than that of losartan non-competitive antagonism),15 losartan and epros- and 10 times greater than the active metabolite of artan are displaced from the AT1 receptor with 7 losartan, EXP-3174. In human resistance vessels, increasing doses of angiotensin II and cause parallel 8 candesartan is 1000 times as potent as losartan. shifts of the dose response without affecting the The comparative potency of the AIIRAs was maximal effect of angiotensin II (competitive or sur- further evaluated in human AT1 receptors, isolated mountable antagonism).10,11,14 Valsartan, irbesartan from a human heart cDNA library and transfected and EXP-3174 (the active metabolite of losartan) 9 into COS-7 cells. The inhibitory effects of EXP- exhibit mixed-type competitive (or surmountable) 3174, eprosartan, irbesartan, candesartan and valsar- and non-competitive (insurmountable) antagonism tan on [I125] angiotensin II receptor binding were 11,12 at the AT1 receptor; telmisartan exhibits insur- compared. The results (Table 1) showed that candes- mountable (non-competitive) but reversible inhibition to angiotensin II-induced contractions in iso- 13 Table 1 Inhibitory effects of various angiotensin II receptor antag- lated rabbit aortic tissue. onists on the specific binding of [I125] angiotensin II to the human The antagonistic properties of candesartan, irbes- AT1 receptor artan, losartan and its active metabolite EXP-3174 were compared by Morsing and colleagues (Figure 16 Compound Inhibition IC50 (nM) 2). The investigations were conducted in isolated preparations of rat portal vein and rabbit thoracic Candesartan 3.0 aortic strips using concentrations of antagonists Irbesartan 8.0 equivalent to the (non-protein-bound) plasma con- EXP-3174 (active metabolite of losartan) 9.2 Eprosartan 53.0 centrations achieved with oral dosing. The study Valsartan 60.0 found similar concentration curves in both rabbit aorta and rat portal vein, which have different tissue 9 Data from Konishi et al. reserves of AT1 receptor. In rabbit aorta, increasing Journal of Human Hypertension The comparative efficacy of candesartan JM Mallion and JP Baguet S35 Figure 2 Angiotensin II-mediated contractile response in isolated rabbit aorta in the presence of (a) candesartan (0.003–1 nM), (b) irbesartan (1–100 nM), (c) losartan (1–100 nM) or (d) EXP-3174 (0.01–1 nM) over 90 min. Reprinted by permission of Elsevier Science from Morsing et al,16 American Journal of Hypertension 11: 37. 1998 by American Journal of Hypertension Ltd. doses of angiotensin II displaced irbesartan (1–100 experimental conditions with drugs such as irbesar- nM), losartan (1–100 nM) and its metabolite EXP- tan may reflect the rate of dissociation from the AT1 3174 (0.1–10 nM) from the AT1 receptor, resulting receptor. When experiments with irbesartan were in parallel shifts in the contractile responses to angi- repeated in isolated rabbit aortic strips after equilib- otensin II. Candesartan (0.03–1 nM) reduced the rium had been reached at 22 h after washout, irbes- maximum response to angiotensin II, causing a artan was shown to have competitive antagonism.16 characteristic non-parallel shift in the dose-response curve of angiotensin II. At 1 nM candesartan, the Kinetics at the AT receptor angiotensin II response was completely suppressed. 1 For irbesartan (100 nM), some degree of suppression Candesartan binds tightly to and dissociates slowly 17 of the angiotensin II response was also recorded at from the AT1 receptor in vitro. These binding the highest concentrations in rabbit aortic strips. characteristics differ from those of losartan, which It is likely that the mixed insurmountable and sur- demonstrates

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